Electroacupuncture enhances anti-tumor immunity in TNBC by reducing NE release and blocking α2-AR-mediated NGF/Hippo signaling.

Electroacupuncture enhances anti-tumor immunity in TNBC by reducing NE release and blockingα2-AR-mediated NGF/Hippo signaling.

Fei-Fei Li, Yan Huang, Chun-Fang Gao, Chun-Yu Wu, Chen-Ping Sun, Yue-Nong Qin, Ying Xie, Sheng Liu, Huan-Gan Wu

Chin Med

Jul 12, 2026

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Abstract

BACKGROUND: Targeting the neuro-immune microenvironment to suppress triple-negative breast cancer (TNBC) represents a critical strategy in tumor immunotherapy. METHODS: A syngeneic 4T1 orthotopic TNBC model in Balb/c mice was employed. EA was applied at ST36 (Zusanli) using systematically optimized parameters (2/15 Hz, 3 mA, 30 min, every other day). Multi-dimensional immunophenotyping by flow cytometry, immunofluorescence, and Western blot was performed across tumor, blood, and splenic compartments. Transcriptome sequencing coupled with KEGG/GSEA pathway analysis was used to identify downstream signaling networks. The NGF/Hippo/YAP axis and adrenergic receptor subtype specificity were validated through pharmacological intervention in vitro, while EA synergy withαPD-L1 was assessed in a CD8T cell-depletion model. RESULTS: ST36 stimulation at 3 mA preferentially suppressed TNBC tumor growth and augmented intratumoral immune infiltration, characterized by elevated CD8T cells, NK cells, and M1-polarized macrophages. EA significantly enhanced CD8T cell effector capacity, upregulating perforin, granzyme B, CD69, and ZAP70 phosphorylation, and synergized withαPD-L1 in a CD8T cell-dependent manner. Mechanistically, EA activated c-Fos/ChATcholinergic neurons in the dorsal motor nucleus of the vagus (DMV) and reduced norepinephrine (NE) output in both circulation and tumors. Transcriptomic profiling identified NGF downregulation and Hippo pathway activation as central events. EA upregulated AMOT, driving YAP phosphorylation at Ser127, cytoplasmic sequestration of YAP, and suppression of downstream IL-6 secretion. In vitro, exogenous NGF suppressed YAP phosphorylation and promoted TNBC malignant behavior, effects fully reversed by the YAP inhibitor verteporfin.α2-adrenergic receptor (α2-AR) antagonism with yohimbine abrogated NE-induced NGF upregulation, pinpointingα2-AR as the receptor subtype linking sympathetic signaling to the NGF/Hippo axis. CONCLUSION: EA at ST36 recalibrates neuro-sympathetic tone in TNBC by activating vagal cholinergic outflow, reducing NE-drivenα2-AR/NGF/Hippo signaling, and thereby relieving immunosuppression while amplifying CD8T cell-mediated cytotoxicity. These findings establish a neuro-immune mechanistic framework for EA-based adjuvant immunotherapy in TNBC.